Project Summary Despite a higher incidence of mood and anxiety disorders in females, and sex differences in the expression of symptoms, the neurobiological underpinnings of sex differences in affective behaviors are not well understood. Dysfunction of the amygdala contributes to these disorders, yet it is unknown whether there are sex differences in amygdala neuronal function, or in amygdala susceptibility in psychopathology. Targeting of sex differences in amygdala pathology is expected to provide a novel therapeutic approach for the treatment of affective disorders. The objective of this project is to test whether differences exist in amygdala physiology and function in females and males, and whether a stress model that shares features with mood disorders exerts sex-dependent effects on the amygdala. This project will test the central hypothesis that the basolateral amygdala (BLA) in females is more responsive than the BLA in males, that this difference is specific for subcircuits of BLA neurons, and that stress decreases neuronal excitability and function of the BLA in females, but exerts opposite effects on BLA function in males. This project will test the contribution of ion channels that regulate BLA neuronal excitability to the sex differences, and key enzymes that modulate the function of these ion channels. In addition, this project will also test whether pharmacological manipulation of these novel ion channel and enzymatic targets reverses the behavioral impact of stress. The rationale for these studies is that the mechanism for sex differences in amygdala-dependent behaviors and the impact of stress on these behaviors is not known. These issues need to be understood to determine the role of the amygdala in sex differences in mood disorder symptomology. The Aims of this proposal are to test if sex differences in BLA neuronal excitability is specific for BLA subcircuits, if the effects of repeated stress on BLA function are sex dependent, and if the effects can be reversed in a sex-dependent manner. This will be tested using in vivo and in vitro electrophysiological approaches, combined with biochemical and behavioral approaches. These Aims are expected to demonstrate sex differences in the physiology of the BLA, the effects of repeated stress on BLA physiology and function, and that pharmacological targeting of the effects of stress will reverse impairments in a sex-dependent manner. This can lead to novel insight into the cause of sex differences in mood and anxiety disorders, and lead to a novel sex-dependent therapeutic approach for rapid treatment of mood disorders.